Only four medications are approved by the Food and Drug Administration (FDA) for the treatment of alcohol dependence (AD), namely disulfiram, naltrexone tablets and injection, and acamprosate, however treatment success has been inconsistent. Thus, there exists a substantial need for discovering ways to provide more effective treatments. Accordingly, identifying new medications for the treatment of AD represents a high priority of National Institute on Alcohol Abuse and Alcoholism (NIAAA) and is a specific research objective of this R21 Program Announcement. Pre-clinical and clinical evidence has clearly demonstrated that the noradrenergic (NE) system is involved in the neurobiology of AD, thus representing an interesting new pharmacotherapy target and the theoretical rationale for this proposal. Consistent with the concept that the NE system may represent a new pharmacological target for AD, recent studies have shown that the prototype a1 NE receptor antagonist prazosin reduces alcohol drinking in different animal models. Furthermore, clinical evidence has also confirmed that prazosin appears to be efficacious in reducing alcohol consumption in alcohol-dependent individuals. While prazosin has a significant side effect profile and must be taken three times a day, no other a1-blockers have been investigated in alcohol research. Prazosin is a short-acting a1-blocker approved to treat hypertension (HTN) and benign prostatic hyperplasia (BPH). After the approval of prazosin in the 70's, other selective a1-blockers have been developed to treat HTN and/or BPH. Among them, doxazosin has shown a more manageable and safer profile than prazosin. In fact, doxazosin is a long-acting a1-blocker, thus it is taken only once/day. Doxazosin is also less likely to give hypotensive side-effects. Thus, doxazosin is more commonly used in clinical practice to treat HTN and/or BPH, than short-acting a1-blockers, such as prazosin. Poor adherence to medications and/or side- effects represent important factors limiting the effectiveness of pharmacotherapies for patients with AD. If effective for AD, doxazosin may represent a simple, manageable and safe medication, which might be more easily transferable to clinical practice. However, doxazosin has never been tested in AD. This project is a 10-week, double-blind, placebo-controlled, between-subject randomized clinical trial with doxazosin (16mg once/day) in alcohol dependent individuals. This study attempts to address whether doxazosin is an effective and safe pharmacotherapy for AD. This Exploratory/Developmental project will serve as the first critical step to explore this hypothesis, and if successful, will lead to a larger and more complex study. The goal of this project is consistent with the need to develop new and more effective treatments for AD. PUBLIC HEALTH RELEVANCE: Alcohol use disorders account for 100,000 excess deaths per year and causes serious morbidity and mortality, increased health care costs and lost work hours. Thus, there exists a substantial need for discovering new, more effective treatments for alcohol use disorders. Blockade of the a1 adrenergic receptors represents a new and promising approach to treat alcohol dependence. Better characterization of this pharmacological approach, by studying the medication doxazosin, may lead to more effective pharmacotherapies for alcohol dependence.